Cocaine addiction is a major problem for which there is no effective therapy. Because addiction is a chronic relapsing illness, characterized by cycles of drug use and abstinence, vaccination against cocaine could be a lifetime therapeutic. The challenge in developing an anti-cocaine vaccine is that cocaine is a small molecule, invisible to the immune system. Previous linking of cocaine as a hapten to a protein carrier has had limited success, likely because the protein carrier has not been sufficiently immunogenic to evoke high affinity, high titer antibodies sufficient to block cocaine from reaching its receptors in the brai. We developed a novel strategy to evoke immunity to cocaine, leveraging the knowledge that adenovirus (Ad) capsid proteins are highly immunogenic in humans. We hypothesized that linking a cocaine analog to Ad capsid proteins would elicit high-affinity, high-titer antibodies against the cocaine, sufficient to sequester systemically administered drug from access to the brain, thus suppressing cocaine-induced behavior. We strategized that we could avoid any risk of the infectious virus by disrupting the Ad, with the concept that a vaccine comprised of the cocaine analog coupled to disrupted capsid proteins would retain the immunologic adjuvant properties of intact Ad. Based on these concepts, we developed dAd5GNE, a disrupted E1- E3- serotype 5 Ad with GNE, a stable cocaine analog, covalently linked to the Ad capsid proteins. In mice, rats and nonhuman pri- mates, dAd5GNE evoked persistent, high titer, high affinity IgG anti-cocaine antibodies. dAd5GNE vaccination was highly effective in abrogating cocaine-induced hyperactivity in mice, following repetitive intravenous doses of cocaine, limiting both hyperactivity and cocaine self-administration behavior in rats, and blocked cocaine access to its cognate CNS receptors in nonhuman primates. The focus of this proposal is to translate dAd5GNE to a clinical study, manufacture GMP grade vaccine, demonstrate safety in experimental animals, obtain regulatory approval and carry out phase I clinical studies to evaluate safety and preliminary measures of efficacy. To accomplish this, we have formulated the following specific aims. Aim 1. Develop a scaled-up process and optimize production, purification and characterization of dAd5GNE, transfer the methods to our GMP facility, validate the manufacturing process, and produce a GMP clinical grade dAd5GNE vaccine. Aim 2. Execute IND-enabling preclinical efficacy and safety testing of the dAd5GNE product. Aim 3. Prepare and submit an IND package and gain approval from the FDA and other regulatory groups to initiate a phase I clinical trial. Aim 4. Carry out a phase I trial to assess the safety nd preliminary measure of efficacy of the dAd5GNE vaccine in humans. PUBLIC HEALTH RELEVANCE: Cocaine addiction is a major health problem for which there is no effective therapy. We have devel- oped an anti-cocaine vaccine dAd5GNE, a highly immunogenic disrupted serotype 5 human adenovi- rus to which a cocaine analog is coupled. Based on studies in mice, rats and nonhuman primates demonstrating dAd5GNE is highly effective in evoking anti-cocaine antibodies and suppressing the ability of cocaine to reach the brain, we propose to carry out the preclinical studies obtain regulatory approval and carry out a phase I safety and initial efficacy trial of dAd5GNE in cocaine addicts.